Abstract: Alzheimer disease (AD) and age-?related macular degeneration (AMD) are two highly debilitating neurological diseases in which the mis-?regulation of biological mechanisms in the aging central nervous system (CNS) leads to expression of certain common disease biomarkers. Citrullination, an irreversible post-?translational protein modification catalyzed by the peptidyl arginine deiminases (PADs) has been linked to pathogenesis in both AD and AMD patients; however, the effort for linking citrullinated retinal targets as biomarkers of AD is not yet established. We recently discovered that early after retinal injury, protein citrullination increases in Muller cells and, in particular, the citrullination of the glial fibrillary acidicprotein(GFAP)wasassociatedwithpathologicalgliosis.Inoriorstudiesweshowedthatinhibition of retinal citrullination potently abrogated expression of citrullinated GFAP isoforms (Mol Vis. 2016 22:1137-?1155), the identification of PAD4 as the inflammation-?inducible PAD enzyme has been key, because it illuminated a novel biomarker and potential druggable target of retinal gliosis (Biochem Biophys Res Commun. 2017 487:134-?139). In pursuing the aims of our R21 grant, we have begun investigating PAD4 expression characteristics in the laser-?injury model of wet-?AMD. In new and exciting preliminary findings, we show that PAD4 expression increases in retinal Muller glia in the laser-?injured retinashowinglocalizationonGFAP-?containingfilaments.GiventhepremisethatPAD4andcitrullinated proteins are increased in human AD brains, we want to ascertain whether this citrullination axis is also activated in the retinas of AD models. For this supplementary grant proposal, we will investigate PAD4 and citrullinated targets in the retinas of established mouse models of AD (3XTg-?AD, Reticulon3 overexpressor, and APP-?PS1 transgenic lines). These studies will help define earliest time points in AD progression when citrullination becomes apparent. This ground-?breaking study will laydown the frameworkforfuturestudiestoidentifyandvalidatenovelretinalbiomarkersofAD.Inaddition,wealso hopetobringinsightintohowcitrullinationleadstoneurodegeneration.Ultimately,identificationofnew retinal biomarkers of AD could afford a clinically relevant means for diagnostics and for monitoring AD therapeuticefficacythroughnon-?invasiveretinalimaging.